Regarding the method for producing optically active 3-methylamino-1-(2-thienyl)-1-propanol derivatives, 1) a method in which an N,N-dimethylamino ketone derivative is subjected to asymmetric reduction and then, after protection of the hydroxy group, subjected to de-methylation, like the following reaction scheme (A) described in Tetrahedron Letters, p. 7101 (1990) or JP-A-4-226948,
and 2) a method in which an N,N-dimethylaminoalcohol derivative is subjected to optical resolution and then, after protection of the hydroxy group, subjected to de-methylation, like the following reaction scheme (B) described in Japanese Patent No. 2,549,681, are known.

However, the method of 1) requires an expensive optically active ligand and results in a low optical yield of about 85%, and the method of 2) wastes half of the substrate due to the optical resolution. In addition, since active zinc is used in the de-methylation step of both 1) and 2), preparation of the reagent is complicated, removal of metal residue and the like after the reaction is necessary and, what is more, protection of hydroxy group is necessary due to aptness of the free hydroxy group at the α-position of the thiophene ring to cause racemization, and because of these troublesome process and the like problems, concern has been directed toward the development of a more inexpensive and convenient production method.
Also, regarding other method for effecting asymmetric reduction of a β-ketocarbonyl compound having thiophene ring, methods which use an Ru-optically active phosphine complex as the catalyst (J. Organometallic Chem., 567, 163 (1998), Tetrahedron Lett., 36, 4801 (1995), C. R. Acad. Sci. Paris, t. 2, Serie IIc, 175 (1999), Tetrahedron, 57, 2563 (2001)) are known, but these have insufficient optical yield and have many unsettled problems in carrying out industrial production.
Also, regarding the method for effecting asymmetric reduction of carbonyl group using a microorganism, various studies have been carried out, but only a method in which 2,5-diacetylthiophene is reduced using baker's yeast (Tetrahedron Asymmetry (1997), 8, 3467) and a method in which trifluoromethyl-(2-thienyl) ketone is reduced using Geotricum candidum (Tetrahedron (1998), 54, 8393) are known as the method for effecting asymmetric reduction of the carbonyl group located at the position adjacent to the thiophene ring, and regarding an optically active 3-hydroxy-3-(2-thienyl)propionic acid ester derivative, its production has been carried out only by a chemical synthesis method which uses an asymmetric catalyst.
Also, as an example which uses an aluminum reducing agent in converting hydroxyalkylamides into hydroxyalkylamines by reducing carbonyl group of the former, a method is known in which a cyclic imide shown in the following reaction scheme (A)
is reduced using sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al (registered trademark)), the aluminum reducing agent is quenched with a sodium hydroxide aqueous solution after completion of the reaction, and then the target product is obtained by carrying out toluene extraction (cf. JP-A-10-168058).
In addition, as an example which uses a borane reducing agent, a method is known in which a cyclic amide is reduced using a borane-dimethyl sulfide complex and then, after completion of the reaction, 5 M hydrochloric acid aqueous solution is added thereto and heated under reflux in order to decompose the boron-amine complex remained in the reaction mixture, thereby decomposing the complex and isolating the hydroxyalkylamine (Tetrahedron Asymmetry, Vol. 5, No. 1, 119 (1994)).
However, when the present inventors have isolated hydroxyalkylamines by the same operation of the former method, it was found that the hydroxyalkylamine as the product is contaminated with a large amount of aluminum originated from the aluminum reducing agent. Since there is a view that aluminum has a possibility of causing Alzheimer disease, it is considered that it is desirable to reduce its contaminating amount as much as possible from a compound to be used as an intermediate of pharmaceutical preparations and agricultural chemicals.
Also, since heat refluxing is carried out using a high concentration hydrohalogenic acid in the latter method, it has a disadvantage in that it cannot be applied to certain substrates having a possibility of causing racemization or dehydration reaction under acidic condition, as well as a possibility of causing corrosion of the reaction vessel, so that this is not desirable industrially. Thus, an industrially useful production method which uses more mild reaction conditions is expected.
The object of the present invention is to provide a method for the industrially convenient and efficient production of optically active γ-hydroxyalkylamines, namely 3-amino-1-(2-thienyl)-1-propanols.